Pharmacology
Summary
NRTIs function as competitive inhibitors for the HIV viral enzyme reverse transcriptase. As nucleotide and nucleoside analogs, they vie with other nucleotides to be integrated into the DNA strand by reverse transcriptase. However, due to the absence of a crucial hydroxyl group at the 3 prime location, DNA chain formation is prematurely terminated when these drugs are incoroprated into the growing strand.
Many of the side effects of NRTIs result from mitochondrial toxicity, which can emerge as peripheral neuropathy, pancreatitis, lipodystrophy, hepatic steatosis, or lactic acidosis. Notable NRTIs include lamivudine, also deployed in treating hepatitis B; emtricitabine, interchangeable with lamivudine; tenofovir, also active against hepatitis B and used as part of the regimen for pre-exposure prophylaxis or PrEP; zidovudine, notorious for myelosuppression; and abacavir, linked with elevated risk of coronary artery disease and a delayed hypersensitivity rash in carriers of HLA-B*5701. NRTIs form the backbone of antiretroviral therapy, which should begin as swiftly as possible following HIV diagnosis.
Lesson Outline
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FAQs
NRTIs, or Nucleoside/Nucleotide Reverse Transcriptase Inhibitors, are used in the treatment of HIV. They function by competitively inhibiting reverse transcriptase – an enzyme needed for the virus to replicate. NRTIs, being nucleotides or nucleoside analogs, incorporate into the growing viral DNA strand. Due to their lack of a 3’ hydroxyl group, no subsequent phosphodiester bond can form, leading to premature chain termination, thereby interfering with the viral replication process.
NRTIs can cause a variety of side effects due to mitochondrial toxicity. These may present as peripheral neuropathy, pancreatitis, lipodystrophy (redistribution of fat from extremities to trunk), hepatic steatosis, and lactic acidosis. Additionally, some specific NRTIs may have unique side effects. For instance, emtricitabine can cause hyperpigmentation of the palms and soles, while tenofovir can increase the risk of kidney injury and bone density loss.
Nucleoside analogs (e.g. lamivudine, emtricitabine, abacavir) require three intracellular phosphorylations by host cell enzymes to become activated. On the other hand, tenofovir, which is a nucleotide analog, requires only two activating phosphorylations.
Lamivudine and tenofovir – both of which are NRTIs – can be used in the treatment of Hepatitis B. In addition to their effectiveness against HIV, these drugs have also shown effectiveness against Hepatitis B.
When initially treating HIV, typically a combination antiretroviral therapy (ART) approach is implemented. This consists of two NRTIs and one integrase inhibitor. This treatment regimen is started as soon as possible following diagnosis. Each NRTI works in a slightly different way to inhibit HIV replication, and the combined use of these drugs offers a more robust approach to inhibition.
